HRP990107A2 - Process for preparing phenoxyphenylsulfonyl halides - Google Patents

Description

Technical problem

This invention relates to a process for the preparation of phenoxyphenylsulfonyl halides, which are useful intermediates for obtaining matrix metalloproteinase inhibitors, and to their intermediates.

Matrix metalloproteinase (MMP) inhibitors are known to be useful in the treatment of conditions selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, joint graft loosening, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and brain aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloidn and angiopathy, nootropic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase inhibition or ADAM expression (including TNF-α). In addition, the products that can be prepared from the compounds and methods of the present invention can be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID, non-steroidal anti-inflammatory drugs), COX-2 inhibitors and analgesics in the treatment of arthritis. , and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.

Matrix metalloproteinase inhibitors are well known in the literature. Specifically, PCT publication WO 96/33172 published October 24, 1996, relates to cyclic arylsulfonylamino hydroxamic acids for use as MMP inhibitors. US patent no. 5,672,615, PCT Publication WO 97/20824, PCT Publication WO 98/08825, PCT Publication WO 98/27069, and PCT Publication WO 98/34918, published Aug. 13, 1998, entitled "Arylsulfonyl Hydroxamic Acid Derivatives" all relate to to cyclic hydroxamic acids used as MMP inhibitors. PCT Publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998, respectively, relate to arylsulfonyl hydroxamic acids. PCT Publication WO 98/03516, published January 29, 1998, relates to phosphinates with MMP activity. PCT Publication WO 98/34915, published August 13, 1998, entitled "N-hydroxy--sulfonyl propionamide derivatives", relates to propionylhydroxamides as useful MMP inhibitors. PCT Publication WO 98/33768, published August 6, 1998, entitled "Arylsulfonylamino hydroxamic acid derivatives", relates to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT Publication WO 98/30566, published July 16, 1998, entitled "Cyclic Sulphone Derivatives", relates to cyclic hydroxamic acid sulfones as MMP inhibitors. US Provisional Patent Application No. 60/55208, filed Aug. 8, 1997, relates to biaryl hydroxamic acids as MMP inhibitors. US Provisional Patent Application No. 60/55207, filed Aug. 8, 1997, entitled "Aryloxyarylsulfonylamino hydroxamic acid derivatives", relates to aryloxyarylsulfonyl hydroxamic acid as MMP inhibitors. US Provisional Patent Application No. 60/62766, filed Oct. 24, 1997, entitled "Use of MMP-13 selective inhibitors in the treatment of osteoarthritis and other MMP-mediated disorders", relates to the use of MMP-13 selective inhibitors in the treatment of inflammation and other disorders. US Provisional Patent Application No. 60/68261, filed Dec. 19, 1997, relates to the use of MMP inhibitors in the treatment of angiogenesis and other disorders. Each of the above publications and applications is incorporated herein in its entirety by reference.

The present inventors have now discovered a suitable process for the preparation of (4-fluorophenoxy-phenyl)-sulfonyl chloride in three steps from 4-chloro-sulfonyl chloride.

The essence of invention

This invention relates to a compound of the formula

[image]

where R is H, Li, Na, K, Mg, or NH4, preferably Na, K, or Mg, most preferably Na.

Other preferred compounds of the invention include compounds of the formula

[image]

where m is an integer from 1-3;

where R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl, preferably fluoro, most preferably where R 2 is in the 4-position of the phenyl ring.

This invention also relates to a process for the preparation of a compound of the formula

[image]

where m is an integer from 1-3;

where R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl;

which contains the reaction of the compound of the formula

[image]

where R 3 is fluoro, chloro or bromo; and R 4 is chloro or bromo;

with the compound formula

[image]

where m is an integer from 1-3, and R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl;

in the presence of a base, preferably potassium t-butoxide, and a solvent, preferably N-methylpyrrolidinone, at a temperature of from 0 °C to about 150 °C.

This invention also relates to a process comprising reacting said compound of formula III with a base, preferably sodium hydroxide, in a solvent, preferably ethanol, at a temperature of about 50°C to about 100°C to form a compound of formula

[image]

where R is H, Li, Na, K or NH4, preferably Na, K or Mg, most preferably Na;

m is an integer from 1-3; and

R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl or perfluoro (C 1 -C 3 )alkyl.

This invention also relates to a process comprising the reaction of a compound of the formula

[image]

where m is an integer from 1-3;

R is H, Li, Na, K or NH4, preferably Na, K or Mg, most preferably Na; and

R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl;

with a halogenating agent, preferably thionyl chloride, in a solvent at a temperature of about 0 °C to about 80 °C to form a compound of the formula

[image]

where m is an integer from 1-3;

R1 is a halide, preferably chloro, and R2 is fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-C3)alkyl, preferably fluoro, chloro, bromo, more preferably fluoro, most preferred where R 2 is in the 4-position of the phenyl ring. Preferably, said reaction is carried out in the presence of a catalyst, preferably dimethylformamide, and a solvent, preferably toluene.

Detailed description of the invention

The following reaction schemes illustrate the preparation of the compounds of this invention. Unless otherwise indicated, R, R1, R2, R3 and R4 in the reaction schemes and discussion that follows are as defined above.

[image]

[image]

Scheme 1 relates to the preparation of a compound of formula I, where R1 is halogen. Compounds of formula I are useful intermediates that can be converted to matrix metalloproteinase inhibitors of formula IX according to the methods of Scheme 2.

According to scheme 1, the compound of formula I is obtained from the compound of formula II by reaction with a halogenating agent, preferably in the presence of a solvent and a catalyst. Suitable halogenating agents include oxalyl chloride, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, preferably thionyl chloride. Suitable catalysts include dimethylformamide. Suitable solvents include toluene, methylene chloride or hexane, preferably toluene. Said reaction is carried out at a temperature of about 0 °C to about 70 °C, the preferred range being between 25 °C and about 60 °C.

Compounds of formula II, where R is hydrogen, sodium, potassium or ammonium (ie H, Li, Na, K or NH4), preferably sodium, can be obtained from compounds of formula II by reaction with a base in a solvent. One skilled in the art will understand that when R is Li, Na, K or NH4, the compound of formula II is ionic, and the R group has a positive charge and the adjacent oxygen atom has a negative charge. Suitable bases include sodium hydroxide, potassium hydroxide or ammonium hydroxide, preferably sodium hydroxide. Suitable solvents include alcohols such as methanol, ethanol, isopropanol, t-butanol or water and mixtures thereof, preferably ethanol. Said reaction is carried out at a temperature of about 0 °C to about 100 °C, the preferred range being between 60 °C to about 80 °C.

A compound of formula III can be obtained by reacting a compound of formula IV with a compound of formula V in the presence of a base in a solvent. Suitable bases include shaded alkoxides or carbonate bases such as potassium t-butoxide, sodium t-amyl oxide or potassium carbonate, preferably potassium t-butoxide. More preferably, two equivalents of potassium t-butoxide are used. Suitable solvents include N-methylpyrrolidinone, dimethyl formamide, dimethylacetamide or diglyme, preferably N-methyl-pyrrolidinone. Said reaction is carried out at a temperature of about 0 °C to about 150 °C, the preferred range being between 25 °C and about 130 °C. It is most preferable that the reaction is carried out at a temperature of about 25 °C for about 1 hour and then the temperature is raised to about 130 °C for about 12 hours.

Compounds of formulas IV and V are commercially available or can be prepared by methods known to those skilled in the art.

Scheme 2 relates to the preparation of matrix metalloproteinase inhibitor compounds of formula XI, where R 6 and R 7 are as defined for the respective groups R 2 and R 3 in PCT publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1996 1998, individually. Compounds of formula VI can be prepared according to PCT Publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998. These publications are hereby incorporated by reference in their entirety.

According to scheme 2, the compounds of the aforementioned formula XI are obtained from the compounds of the formula IX by reaction with a chlorinating agent such as, for example, oxalyl chloride or thionyl chloride, preferably oxalyl chloride, and a catalytic amount, preferably about 2%, of N,N-dimethylformamide in inert solvent such as methylene chloride or toluene to form in situ the acid chloride of formula X which later reacts with the in situ formed silylated hydroxylamine. Silated hydroxylamine formed in situ is obtained by reacting hydroxylamine hydrochloride or hydroxylamine sulfate, preferably hydroxylamine hydrochloride, with trimethylsilyl chloride in the presence of a base such as pyridine, 2,6-lutidine, or diisopropylethylamine, preferably a pyridine solvent. A suitable in situ formed silylated hydroxylamine is selected from O-trimethylsilylhydroxylamine, N,O-bistrimethylsilylhydroxylamine or combinations thereof. The reaction is carried out at a temperature of about 0°C to about 22°C (ie, room temperature) for about 1 to about 12 hours, preferably about 1 hour.

Compounds of formula IX can be prepared from compounds of formula VIII by reduction in a polar solvent. Suitable reducing agents include palladium catalysts, such as hydrogen over palladium, hydrogen over palladium on carbon or hydrogen over palladium hydroxide on carbon, preferably hydrogen over palladium on carbon. Suitable solvents include tetrahydrofuran, methanol, ethanol and isopropanol and mixtures thereof, preferably ethanol. The mentioned reaction is carried out at a temperature of about 22 °C (ie room temperature) for a period of 1 to 7 days, preferably about 2 days.

Compounds of formula VIII can be obtained from compounds of formula VII, where R5 is optionally substituted benzyl, by Michael addition to a propiolate ester with a base in a polar solvent. Suitable propiolates are those of the formula H-C≡C-CO2R8, where R8 is (C1-C6)alkyl. Suitable bases include tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, preferably tetrabutylammonium fluoride. Suitable solvents include tetrahydrofuran, acetonitrile, tert-butanol, t-amyl alcohols and N,N-dimethylformamide, preferably tetrahydrofuran. Said reaction is carried out at a temperature of about -10°C to about 60°C, the preferred range being between 0°C and about 22°C (ie, room temperature). Compounds of formula VIII are obtained as mixtures of geometric isomers around an olefinic double bond; isomer separation is not necessary.

Compounds of formula VII can be obtained by reacting compounds of formula VI with compounds of formula I, from scheme 1, in the presence of a base in a solvent. Suitable bases include triethylamine, diisopropylethylamine, preferably triethylamine. Suitable solvents include toluene, or methylene chloride, preferably toluene.

The final products of formula XI can also be saponified to the free acid using a base such as sodium hydroxide in a protic solvent such as ethanol, methanol or water or a mixture such as water and ethanol, water and toluene, or water and THF. The preferred solvent system is water and toluene. The reaction is carried out over a period of 30 minutes to 24 hours, preferably around 2 hours.

Compounds of formula XI, which are basic in nature, are capable of forming a large number of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for use in animals, it is often desirable in practice to first isolate the compound of formula XI from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it to the free base compound by treatment with an alkaline reagent, and later convert the free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with an actual equivalent amount of a selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

The acids used for the preparation of pharmaceutically acceptable acid addition salts from the basic compounds of this invention are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of formula XI which are also acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include salts of alkali or alkaline earth metals and, in particular, sodium and potassium salts. These salts are all prepared using conventional techniques. Chemical bases used as reagents for the preparation of pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acid compounds of formula XI described herein. These non-toxic basic salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can be readily obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be obtained by combining solutions of acidic compounds in a lower alkanol and alkoxide of the desired alkali metal, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of reagents are preferably used to ensure completeness of the reaction and maximum product yields.

The ability of compounds of formula XI or their pharmaceutically acceptable salts (hereinafter also referred to as active compounds) to inhibit matrix metalloproteinases or tumor necrosis factor (TNF) production and, therefore, to demonstrate their effectiveness in the treatment of diseases characterized by matrix metalloproteinase or tumor necrosis factor production is can be determined according to in vitro analytical tests well known to those skilled in the art. One example of a test that confirms that the final products are produced by the methods of the invention is the human collagenase inhibition test.

BIOLOGICAL EXPERIMENT

Inhibition of human collagenase (MMP-1)

Human recombinant collagenase is activated by trypsin using the following ratio: 10 µg of trypsin per 100 µg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes, then a fivefold excess (50 µg/10 µg trypsin) of soy trypsin inhibitor is added.

10 mM inhibitor solution is already prepared in dimethyl sulfoxide and then diluted according to the following scheme:

10 mM → 120 µM → 12 µM → 1.2 µM → 0.12 µM

Twenty-five microliters of each concentration is then added in triplicate to the appropriate well of a 96-well microfluor plate. The final inhibitor concentration will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are placed in slots D1-D6 and blanks (no enzyme, no inhibitor) are placed in slots D7-D12.

Collagenase is diluted to 400 ng/ml and then 25 µl is added to the corresponding openings of the microfluor plate. The final concentration of collagenase in the test is 100 ng/ml.

The substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) was prepared as a 5 mM solution in dimethyl sulfoxide and then diluted to 20 mM in assay buffer. The test starts with the addition of 50 μl of substrate per microfluor plate opening to obtain a final concentration of 10 μM.

Fluorescence readings (excitation 360 nm, emission 460 nm) are taken at time 0 and then at 20 minute intervals. The test is performed at room temperature with a typical test time of 3 hours.

The ratio of fluorescence versus time is then plotted graphically for both blanks and collagenase-containing samples (data from triplicate determinations are averaged). The time point at which a good signal is obtained (initial signal) and which is on the linear part of the curve (usually around 120 minutes) is chosen to determine the IC50 value. Zero time is used as the initial signal for each compound at each concentration and these values are subtracted from the data for 120 minutes. The data are entered in the diagram as the concentration of the inhibitor in % of the control sample (fluorescence of the inhibitor divided by the fluorescence of the collagenase itself × 100). IC50 values are determined from the inhibitor concentration that gives a signal as 50% of the control sample.

If the IC50 values are <0.03 µM, then the inhibitors are tested at concentrations of 0.3 µM, 0.03 µM, 0.03 µM and 0.003 µM.

The following examples demonstrate the preparation of the compounds of this invention. Melting points are not corrected. NMR data are expressed in parts per million (δ) and refer to the initial deuterium signal from the sample solvent (deuteriochloroform unless otherwise noted). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm silica gel and performed under nitrogen pressure conditions (flash chromatography). Room or ambient temperature means 20-25 °C. All anhydrous reactions were carried out under a nitrogen atmosphere for convenience and to increase yields. Concentration at reduced pressure means that a rotary evaporator is used.

Example 1

4-fluorophenyl ester of 4-(4-fluorophenoxy)benzenesulfonic acid

A solution of 14.68 g (0.131 mol, 2.0 equivalents) of potassium tert-butoxide in 27 ml of dry N-methylpyrrolidinone is treated with a solution of 15.39 g (0.137 mol, 2.1 equivalents) of 4-fluorophenol in 27 ml of dry of N-methylpyrrolidinone at room temperature, which causes a slight release of heat up to 45 °C. A solution of 13.81 g (0.065 mol) of 4-chlorobenzenesulfonyl chloride in 27 ml of dry N-methylpyrrolidinone was slowly added to the dark reaction mixture causing a slight release of heat up to 44 °C. The resulting mixture was stirred at room temperature for 1 hour and then at 130 °C for 11 hours. The cooled reaction mixture is treated with 162 ml of water, seeded with traces of 4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester, and granulated at room temperature overnight. The resulting solid was filtered to give 20.24 g (85%) of 4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester.

1 H NMR (CDCl 3 ) δ 7.74 (dd, J=7.0, 2.0 Hz, 2H); 7.14-6.97 (m, 10H). Melting point 78-83 °C.

Example 2

4-(4-fluorophenoxy)benzenesulfonic acid, sodium salt

To a slurry consisting of 47.43 g (0.131 mol) of 4-fluorophenyl ester of 4-(4-fluorophenoxy)benzenesulfonic acid in 475 ml of ethanol is added 13.09 g (0.327 mol, 2.5 equivalents) of sodium hydroxide pellets. . This mixture is heated under reflux for 3 hours and stirred overnight at room temperature. The resulting solid was filtered to give 37.16 g (98%) of the sodium salt of 4-(4-fluorophenoxy)benzenesulfonic acid.

1H NMR (CD3OD) δ 7.73-7.78 (m, 2H); 7.05-7.13 (m, 2H); 6.99-7.05 (m, 2H); 6.90-6.95 (m, 2H).

Example 3

4-(4-fluorophenoxy)benzenesulfonyl chloride

11.3 ml (0.155 mol, 3 equivalents) of thionyl chloride and 0.04 ml (0.5 mmol, 0.01 equivalent) of dimethylformamide. The resulting mixture is stirred at room temperature for 48 hours, filtered through diatomaceous earth, and concentrated under reduced pressure to 40 ml. This solution was used without further purification for the preparation of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid benzyl ester.

A 5.0 ml portion of this solution was concentrated to 1.77 g of 4-(4-fluorophenoxy)benzenesulfonyl chloride as an oil, corresponding to a 96% yield.

1 H NMR (CDCl 3 ) δ 7.92-7.97 (m, 2H); 7.01-7.13 (m, 6H). A portion of similarly prepared oil is crystallized from hexane, melting point 80 °C.

Preparation 1

3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]propionic acid

A) Benzyl ester of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid

Mixtures of 12.41 g (0.032 mol) of 1-aminocyclopentanecarboxylic acid benzyl ester, as the toluene-4-sulfonic acid salt, (can be prepared by methods such as those described in US Pat. No. 4,745,124) and 10.0 g (0.035 mol, 1.1 equivalent) of 4-(4-fluorophenoxy)benzenesulfonyl chloride (prepared according to preparation 3) in 113 ml of toluene is added 11.0 ml (0.079 mol, 2.5 equivalent) of triethylamine. The resulting mixture was stirred at room temperature overnight, washed with 2N hydrochloric acid (2 x 100 ml) and brine (100 ml), dried over sodium sulfate, and concentrated to 30 ml. Hexane, 149 ml, was added dropwise over 3 hours to form a solid precipitate which was granulated at 0 °C over 1 hour and filtered to give 12.59 g (85%) of 1-[4-(4-fluorophenoxy) benzyl ester. )benzenesulfonylamino]cyclopentane-carboxylic acids.

1 H NMR (CDCl 3 ) δ 7.78-7.82 (m, 2H); 7.30-7.39 (m, 5H); 7.06-7.12 (m, 2H); 6.99-7.04 (m, 2H); 6.93-6.97 (m, 2H); 5.15 (s, 1H); 5.02 (s, 2H); 2.04-2.13 (m, 2H); 1.92-1.98 (m, 2H); 1.62-1.69 (m, 4H).

4.0 g of the sample was granulated in a mixture of 4 ml of ethyl acetate and 40 ml of hexane overnight to give 3.72 g (93 % recovery) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid benzyl ester as a pale yellow solids, melting point 97.0-97.5 °C.

B) Benzyl ester of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentane-carboxylic acid

A solution of 25.0 g (53.2 mmol) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid benzyl ester and 10.8 ml (106 mmol, 2 equivalents) of ethyl propiolate in 200 ml of dry tetrahydrofuran at 1 °C is treated with 53.2 ml (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M) for 45 minutes. The resulting solution is allowed to slowly warm to room temperature and stirred overnight. Tetrahydrofuran is removed using toluene under reduced pressure, and the toluene solution is washed with water and brine, diluted to 600 ml with toluene, mixed with 90 g of silica gel for 3 hours, filtered and concentrated to 25.14 g (83%) of benzyl 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid ester as an orange oil. 1H NMR (CDCl3) showed a 1.5:1 ratio of trans/cis forms.

Trans δ 7.74-7.78 (m, 2H); 7.72 (d, J=14 Hz, 1H); 7.26-7.36 (m, 5H); 6.96-7.12 (m, 4H); 6.78-6.84 (m, 2H); 5.44 (d, J=14 Hz, 1H); 5.11 (s, 2H); 4.12 (q, J=7.1 Hz, 2H); 2.08-2.43 (m, 4H); 1.63-1.80 (m, 4H); 1.24 (t, J=7.1 Hz, 3H).

Cis δ 7.68-7.72 (m, 2H); 7.26-7.36 (m, 5H); 6.96-7.12 (m, 4H); 6.86-6.91 (m, 2H); 6.47 (d, J=8.1 Hz, 1H); 5.90 (d, J=8.1 Hz, 1H); 5.11 (s, 2H); 3.93 (q, J=7.2 Hz, 2H); 2.08-2.43 (m, 4H); 1.63-1.80 (m, 4H); 1.17 (t, J=7.2 Hz, 3H).

C) {(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid

A solution of 2.50 g (4.4 mmol) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester in 25 ml of ethanol is treated with 2.5 g of 50 % wet 10% palladium on carbon catalyst and shake under 3.654221365 bar (53 psi) hydrogen for 21 hrs. The catalyst was removed by filtration and washed with ethanol (4 x 25 ml). The filtrate and washings were combined and concentrated in vacuo to 1.74 g (82%) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid as a viscous oil.

1 H NMR (CDCl 3 ) δ 7.78-7.82 (m, 2H); 6.94-7.09 (m, 6H); 4.09 (q, J=7.2 Hz, 2H); 3.56-3.60 (m, 2H); 2.75-2.79 (m, 2H); 2.33-2.39 (m, 2H); 1.93-2.03 (m, 2H); 1.69-1.76 (m, 2H); 1.56-1.63 (m, 2H); 1.22 (t, J=7.2 Hz, 3H).

D) {(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid,

dicyclohexylamine salt

A solution of 3.10 g (6.5 mmol) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid in 30 ml of ethanol is treated with 1.28 ml (6, 5 mmol, 1 equivalent) of dicyclohexylamine at room temperature where a solid forms within 5 minutes. This mixture was stirred at room temperature overnight and then at 0 °C for 5 hours. The white solid is isolated by filtration, washed with 10 ml of cold ethanol, and air-dried to give 2.89 g (67%) of the dicyclohexylamine salt of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino }cyclopentanecarboxylic acids.

1H NMR (CDCl 3 ) δ 7.86-7.91 (m, 2H); 6.99-7.09 (m, 4H); 6.90-6.94 (m, 2H); 5.3 (no. s, 2H); 4.07 (q, J=7.1 Hz, 2H); 3.54-3.59 (m, 2H); 2.88-2.95 (m, 4H); 2.31-2.38 (m, 2H); 1.95-2.22 (m, 6H); 1.68-1.77 (m, 6H); 1.53-1.60 (m, 4H); 1.40-1.50 (m, 4H); 1.21 (t, J=7.1 Hz, 3H); 1.14-1.22 (m, 6H). Melting point 164.5-165.9 °C.

E) {(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid

A solution of 3.0 g (4.5 mmol) of the dicyclohexylaminium salt of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid in 30 ml of dichloromethane is treated with 30 ml of 2N hydrochloric acid. at room temperature which causes immediate precipitation of the solid. This mixture was stirred at room temperature for 3 hours. The solid is filtered, the aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with water, dried over sodium sulfate, and concentrated in vacuo to 2.2 g (100%) of 1-{(2-ethoxycarbonylethyl)-[4- (4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid as a clear oil.

1H NMR (DMSO-d6) δ 12.68 (bs, 1H); 7.76-7.80 (m, 2H); 7.25-7.31 (m, 2H); 7.16-7.21 (m, 2H); 7.03-7.08 (m, 2H); 4.01 (q, J=7.1 Hz, 2H); 3.48-3.54 (m, 2H); 2.64-2.70 (m, 2H); 2.13-2.21 (m, 2H); 1.90-1.98 (m, 2H); 1.52-1.59 (m, 4H); 1.14 (t, J=7.1 Hz, 3H).

F) Ethyl ester of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid

A solution of 7.26 g (15.1 mmol) of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino} cyclopentanecarboxylic acid in 73 ml of dichloromethane is treated with 1.4 ml (17 mmol , 1.1 equiv) of oxalyl chloride and 0.02 ml (0.3 mmol, 0.02 equiv) of dimethylformamide at room temperature, causing some foaming, and stirred overnight. The resulting solution of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)-benzenesulfonyl]amino}propionic acid ethyl ester was used to prepare 3-[[4-(4-fluorophenoxy)-benzenesulfonyl]-( 1-Hydroxycarbamoylcyclopentyl)amino] propionic acid without isolation.

A similarly prepared solution of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid ethyl ester is concentrated in vacuo to an oil.

1H NMR (CDCl 3 ) δ 7.84-7.87 (m, 2H); 6.97-7.12 (m, 6H); 4.10 (q, J=7.2 Hz, 2H); 3.55-3.59 (m, 2H); 2.68-2.72 (m, 2H); 2.47-2.53 (m, 2H); 1.95-2.02 (m, 2H); 1.71-1.76 (m, 4H); 1.24 (t, J=7.2 Hz, 3H).

G) Ethyl ester of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid

A solution of 1.37 g (19.7 mmol, 1.3 equiv) of hydroxylamine hydrochloride in 9.2 ml (114 mmol, 7.5 equiv) of dry pyridine at 0 °C is treated with 5.8 ml (45 mmol, 3 .0 equiv) of trimethylsilyl chloride, causing a white solid to precipitate, and allowed to warm to room temperature overnight. This mixture was then cooled to 0 °C and treated with a solution of 7.54 g (15.1 mmol) of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)-benzenesulfonyl]amino}propionic acid ethyl ester in 73 ml of dichloromethane, prepared as described above, without insulation, which causes the release of heat up to 8 °C. This mixture is stirred at 0 °C for 30 minutes and at room temperature for about 1 hour. The reaction mixture is then treated with 50 ml of 2N aqueous hydrochloric acid and stirred at room temperature for 1 hour. The aqueous phase was extracted with dichloromethane and the combined organic extracts were washed with 2N aqueous hydrochloric acid (2 x 50 ml) and water (50 ml). This solution of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was used to prepare 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1- hydroxy carbamoylcyclopentyl)amino]-propionic acid without isolation. The aliquot is concentrated to a spongy mass.

1H NMR (DMSO-d6) δ 10.37 (s, 1H); 8.76 (s, 1H); 7.74-7.79 (m, 2H); 7.24-7.30 (m, 2H); 7.14-7.20 (m, 2H); 7.01-7.05 (m, 2H); 3.99 (q, J=7.1 Hz, 2H); 3.42-3.47 (m, 2H); 2.62-2.67 (m, 2H); 2.16-2.23 (m, 2H); 1.77-1.85 (m, 2H); 1.43-1.52 (m, 4H); 1.13 (t, J=7.1 Hz, 3H).

A similarly prepared solution is concentrated in vacuo to 6.71 g (89 %) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester as a hard dry spongy mass.

H) [[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid

A solution of 7.48 g (15.1 mmol) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)amino]propionic acid ethyl ester in dichloromethane is concentrated by rotary evaporation with the addition of 75 ml of toluene. This solution was treated with 75 ml of water, cooled to 0 °C, and then treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets for 10 min with vigorous stirring. This mixture was stirred for 15 minutes at 0 °C and warmed to room temperature over 1 hour. The aqueous phase is separated, diluted with 7.5 ml of tetrahydrofuran, cooled to 0 °C, and treated with 33 ml of 6N aqueous hydrochloric acid for 20 minutes. This mixture is stirred with 75 ml of ethyl acetate at 0 °C to room temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution is slowly treated with 150 ml of hexane at room temperature causing a solid to precipitate, and stirred overnight. Filtration gives 5.01 g of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid as a white solid (71% yield from 1-{(2-ethoxycarbonylethyl)-[4- (4-fluorophenoxy)benzenesulfonyl]amino}cyclopentane carboxylic acids).

1H NMR (DMSO-d6) δ 12.32 (s, 1H); 10.43 (s, 1H); 8.80 (s, 1H); 7.82 (d, J=8.6 Hz, 2H); 7.28-7.35 (m, 2H); 7.20-7.26 (m, 2H); 7.08 (d, J=8.9 Hz, 2H); 3.44-3.49 (m, 2H); 2.61-2.66 (m, 2H); 2.24-2.29 (m, 2H); 1.86-1.90 (m, 2H); 1.54-1.55 (m, 4H). Melting point 162.9-163.5 °C (declared).

Claims (15)

1. Compound formula [image] wherein R is H, Li, Na, K, Mg, or NH 4 . 2. Compound formula [image] indicated by the fact that m is an integer from 1-3; R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl or perfluoro (C 1 -C 3 )alkyl. 3. A compound according to claim 2, characterized in that R2 is fluoro. 4. Compound according to claim 3, characterized in that R2 is in the 4-position of the phenyl ring. 5. Procedure for the preparation of the compound of the formula [image] where m is an integer from 1-3; R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl; characterized by the fact that it contains the reaction of the compound of the formula [image] where R 3 is fluoro, chloro or bromo; and R 4 is chloro or bromo; with the compound formula [image] where m is an integer from 1-3; and R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl; in the presence of a base and a solvent at a temperature from 0 °C to about 150 °C. 6. The method according to claim 5, characterized in that said base is potassium t-butoxide and said solvent is N-methylpyrrolidinone. 7. The method according to claim 5, characterized in that it further comprises the reaction of said compound of formula III with a base in a solvent at a temperature of about 50 °C to about 100 °C to form a compound of formula [image] where m is an integer from 1-3; R is H, Li, Na, K or NH4; and R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl or perfluoro (C 1 -C 3 )alkyl. 8. The method according to claim 7, characterized in that said base is sodium hydroxide and said solvent is ethanol. 9. The method according to claim 7, characterized in that it further contains the reaction of the compound of the formula [image] where m is an integer from 1-3; R is H, Li, Na, K or NH4; and R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl; with a halogenating agent in a solvent at a temperature of about 0 °C to about 80 °C to form a compound of the formula [image] where R1 is a halide and m is an integer from 1-3. 10. The method according to claim 9, characterized in that R1 is chloro. 11. The method according to claim 9, characterized in that R2 is fluoro. 12. The method according to claim 9, characterized in that R2 is in the 4-position of the phenyl ring. 13. The method according to claim 9, characterized in that said halogenating agent is thionyl chloride. 14. The method according to claim 9, characterized in that it further contains the addition of a catalyst and a solvent. 15. The method according to claim 14, characterized in that said catalyst is dimethylformamide and said solvent is toluene.